Dendritic cells (DCs) play a pivotal role in the functional differentiation of CD4+ T cells in response to pathogens. In CD4+ T cells, HIV-1 replicates efficiently, while HIV-2, a related virus of reduced pathogenicity, is better controlled. How the DC response to HIV-1 vs HIV-2 contributes to programming an antiviral state in CD4+ T cells is not known. Here, we identify a transcriptional signature associated with progressive resistance to HIV infection in CD4+ T cells. We developed a model of naïve CD4+ T cell priming by DCs stimulated with a panel of seven viruses or synthetic ligands for the viral nucleic acid sensors cGAS and TLRs. DCs produced a cytokine response to HIV-2 infection more similar to the response to cGAS ligands than TLR ligands. In response to these signals, naive CD4+ T cells acquired a gradual antiviral resistance to subsequent HIV infection. The antiviral state was concomitant with the induction of the TH1 cytokine IFNγ and the type I interferon-stimulated gene (ISG) MX1, while the TFH cytokine IL-21 was not increased. By performing a transcriptional network analysis in T cells, we identified five distinct gene modules with characteristic ISG, TH1, TFH, IFN-I and proliferative signatures. Finally, we leverage this module to assemble a T antiviral signature of 404 genes that correlate with the antiviral state in T cells. Altogether, the study illuminates the programming of the antiviral state in T cells. The T antiviral gene signature in human CD4+ lymphocytes constitutes a resource for genetic screens and genomics analysis.
Keywords: CD4+ T cells; HIV; antiviral state; dendritic cells; gene signature.
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